This invention relates to an anti-inflammatory and analgesic pharmaceutical reparation for external use having excellent percutaneous absorption and applicability.
Non-steroidal anti-inflammatory and analgesic agents have an excellent anti-inflammatory and analgesic activity and have been widely used clinically in such dosage forms as ointments, gels, creams, lotions, adhesive plasters, capsules, suppositories and injections.
It has been hitherto common that non-steroidal anti-inflammatory and analgesic agents (hereinafter referred to as NSAIDs) have been orally administered in the dosage form of capsules, tablets, etc. Although oral dosage forms can be very effective when absorbed from the gastrointestinal tract, they can produce significant side effects. Therefore, oral dosage forms must be used with careful monitoring. Accordingly, to reduce side effects, such as gastrointestinal disorders, topical dosage forms have been developed, for example, gels (Japanese Patent Kokai Application No. 161323/1981), creams (Japanese Patent Kokai Application Nos. 103811/1983 and 298526/1987), ointments (Japanese Patent Kokai Application No. 39616/1983), adhesive plasters (Japanese Patent Kokai Application No. 250317/1989) and others. However, these prior art inventions have not resolved the problems of poor diffusion and transfer of the NSAIDs in the base phase of the adhesive plasters and inadequate drug release and percutaneous absorption from ointments (gel bases).
Accordingly, it is an object of this invention to provide a cutaneous pharmaceutical preparation for external use wherein the percutaneous absorption of NSAIDs is improved.
As a result of intensive studies carried out by the present inventors, it has been discovered that the percutaneous absorption of an NSAID is significantly improved by adding to a specific water-soluble base a percutaneous absorption promoting agent selected from the group consisting of oleic acid, oleyl alcohol and mixtures thereof.
More specifically, the present invention relates to a pharmaceutical preparation for external use which comprises an NSAID and as a percutaneous absorption promoting agent, oleic acid, oleyl alcohol or a mixture thereof, in a pharmaceutically acceptable aqueous alcoholic solvent.
As the aqueous alcoholic solvent employed in this invention, there may be preferably mentioned a homogeneous mixed solvent comprising a monohydric saturated aliphatic alcohol of 1-4 carbon atoms; a polyhydric alcohol selected from the group consisting of saturated aliphatic glycols of 2-4 carbon atoms, glycerol and mixtures thereof; and water.
As the monohydric saturated aliphatic alcohol, there may be mentioned: methanol, ethanol, n-propanol, isopropanol and the like. Ethanol and isopropanol are particularly preferred.
As the saturated aliphatic glycol, there may be mentioned: ethylene glycol, propylene glycol, 1,3-butylene glycol, isopropylene glycol (3-methyl-1,3-butanediol) and the like.
As the polyhydric alcohol, there may be mentioned: said saturated aliphatic glycol of 2-4 carbon atoms and/or glycerol. Glycerol is particularly preferred.
A preferable blended proportion of such aqueous alcoholic solvent is 15-70% by weight, more preferably 30-65% by weight, for the monohydric saturated alcohol, 0.1-30% by weight, more preferably 0.5-15% by weight, for the polyhydric alcohol and 10-60% by weight preferably 20-50% by weight, for water. When the proportion of the monohydric saturated aliphatic alcohol is too low, solubility of the NSAIDs is lowered, whereby turbidity appears and stability is decreased. The polyhydric alcohol, more preferably glycerol, may be preferably used at 5-30% by weight to the said monohydric saturated alcohol while satisfying said blended proportion.
It is essential in this invention to combine the specified aqueous alcoholic solvent with oleic acid and/or oleyl alcohol. These percutaneous absorption promoting agents may be used alone or in combination.
Oleic acid is preferred and cis-oleic acid is most preferred. A blended proportion of such percutaneous absorption promoting agents is 0.1-15% by weight. preferably, 0.5-10% by weight, based on the total weight of the preparation for external use. If it is too low, a promoting effect on percutaneous absorption will not be obtained.
Increasing the concentration of the percutaneous absorption promoting agent above 15% does not afford a significant improvement in percutaneous absorption.
The NSAID may be preferably employed at a concentration of 0.1-10% by weight, more preferably at a concentration of 0.5-5% by weight, based upon the total weight of the preparation for external use.
It is preferable for the anti-inflammatory and analgesic preparation for external use to further incorporate therein menthol, especially 1-menthol. Menthol may be employed in a concentration of 0.5-5% by weight, based upon the total weight of the preparation for external use.
The anti-inflammatory and analgesic pharmaceutical preparation of this invention may be preferably applied in the dosage form of liquids or gels as such dosage forms permit more effective use of the present invention. These dosage forms may use conventional bases and blending components compliant with the desired dosage form. As the water-soluble polymers which may be commonly used as a gelling agent there may be mentioned, for example, carboxyvinyl polmer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc. The gelling agent may be employed in a concentration of 0.1-5% by weight, based upon the total weight of the preparation for external use.
If required, humectants, antiseptics, antioxidants, coloring agents, perfumes, thickening agents, etc., may optionally be added to the anti-inflammatory and analgesic pharmaceutical preparation of this invention.
In accordance with this invention, there is provided a cutaneous, NSAID containing, topical pharmaceutical preparation that has excellent percutanous absorption. Significantly, the dermatologic, topical, NSAID containing pharmaceutical preparation of the present invention possesses excellent percutaneous absorptive properties and when used in therapy can reduce NSAID side effects, such as, gastrointestinal, hepatic and renal disorders caused by continued oral administration and avoid the pain accompanying NSAID injection. The use of the dermatologic topical preparations of the present invention affords potent therapeutic effects in chronic articular rheumatish, peritendinitis, muscle pain, swelling and pain after wounds, etc.